Foldamer-Mediated Structural Rearrangement Attenuates Aβ Oligomerization and Cytotoxicity

The conversion of the native random coil amyloid beta (A beta) into amyloid fibers is thought to be a key event in the progression of Alzheimer's disease (AD). A significant body of evidence suggests that the highly dynamic A beta oligomers are the main causal agent associated with the onset of AD. Among many potential therapeutic approaches, one is the Modulation of A beta conformation into off-pathway structures to avoid the formation of the putative neurotoxic A beta oligomers. A library of oligoquinolines was screened to identify antagonists of A beta oligomerization, amyloid formation, and cytotoxicity. A dianionic tetraquinoline, denoted as 5, was one of the most potent antagonists of A beta fibrillation. Biophysical assays including amyloid kinetics, dot blot, ELISA, and TEM show that 5 effectively inhibits both A beta oligomerization and fibrillation. The antagonist activity of 5 toward A beta aggregation diminishes with sequence and positional changes in the surface functionalities. 5 binds to the central discordant alpha-helical region and induces a unique a-helical conformation in A beta. Interestingly, 5 adjusts its conformation to optimize the antagonist activity against A beta. 5 effectively rescues neuroblastoma cells from A beta-mediated cytotoxicity and antagonizes fibrillation and cytotoxicity pathways of secondary nucleation induced by seeding. 5 is also equally effective in inhibiting preformed oligomer-mediated processes. Collectively, 5 induces strong secondary structure in A beta and inhibits its functions including oligomerization, fibrillation, and cytotoxicity.